Gastro-Intestinal Hormones & Transmitters

3
CHAPTER
Gastrointestinal Hormones and Neurotransmitters

Rodger A. Liddle
CHAPTER OUTLINE
Cellular Communication Neural Regulation of the Gastrointestinal Tract Peptide Hormones of the Gastrointestinal Tract
Synthesis, Post-translational Modication, and Secretion Gastrin Cholecystokinin Secretin Vasoactive Intestinal Polypeptide Glucagon Glucose Dependent-Insulinotropic Polypeptide Pancreatic Polypeptide Family Substance P and the Tachykinins Somatostatin Motilin Leptin Ghrelin 3 4 6 6 7 8 8 8 9 9 9 10 10 10 11 11 11 12 12 12 13 Nitric Oxide Adenosine Cytokines 14 14 14 14 15 15 16 17 17 18 18 18 18 18 19 19 19 19 20
Signal Transduction
G Protein-Coupled Receptors G Proteins Receptors Not Coupled to G Proteins
Regulation of Gastrointestinal Growth by Hormones and Transmitters

Growth Factor Receptors Epidermal Growth Factor Transforming Growth Factor-a Transforming Growth Factor-b Insulin-Like Growth Factor Fibroblast Growth Factor and Platelet-Derived Growth Factor Trefoil Factors Other G Protein-Coupled Receptors and Growth
Other Chemical Messengers of the Gastrointestinal Tract

Acetylcholine Catecholamines Serotonin Histamine
Regulation of Gastrointestinal Hormones by Intraluminal Releasing Factors Gastrointestinal Peptides That Regulate Satiety and Hunger Entero-insular Axis
Cells throughout the gastrointestinal tract receive information in many forms, including chemical messengers that emanate from other cells. The initial stimulus for hormone secretion is the ingestion of food. Food provides central neural stimulation in the form of thought (anticipation) and sight, chemical stimulation in the form of odor and taste, nutrient stimulation of the epithelial cells lining the gastrointestinal tract, and mechanical stimulation. These processes all stimulate the release of peptides and other transmitters from cells of the mucosa either into the nearby space, where they act locally, or into the bloodstream, where they circulate to distant target tissues. Therefore, chemical messengers from the gastrointestinal tract can have far-reaching effects throughout the body.
CELLULAR COMMUNICATION
Chemical transmitters of the gut are produced by discrete cells of the gastrointestinal mucosa and can be classied as endocrine, paracrine, synaptic (neurocrine), or autocrine (Fig. 11). Specialized signaling cells that secrete transmitters into the blood are known as endocrine cells, and the transmitters they produce are known as hormones. Hormones bind to specic receptors on the surface of target cells at remote sites and regulate metabolic processes.1 In contrast with endocrine cells that act on distant target tissues, other signaling cells of the gastrointestinal tract may produce transmitters that act on neighboring cells.
Section I Biology of the Gastrointestinal Tract and Liver

ferent hormones into the blood, and their actions depend on the specicity of the receptor on the target tissues. In contrast, in synaptic transmission the variety of neurotransmitters is more limited, and the specicity of action is dependent on the precise location where the nerves synapse with the target cells. The concentration of signaling molecules can be adjusted quickly because the transmitter can be rapidly metabolized. In the synaptic cleft, transmitters are either rapidly destroyed or taken back up by the secretory neuron. Concentrations of these peptides can be regulated rapidly by changes in their rate of synthesis, secretion, or catabolism. Many peptide transmitters have extremely short half-lives (generally on the order of minutes); this fact allows the rapid initiation and termination of signaling. Endocrine transmitters of the gastrointestinal tract consist predominantly of peptides (e.g., gastrin, secretin, etc.). Paracrine transmitters can be peptides such as somatostatin or nonpeptides such as histamine that act locally on neighboring cells. Neurotransmitters can be peptides such as vasoactive intestinal polypeptide (VIP) and tachykinins or small molecules such as acetylcholine and epinephrine that are secreted, or nitric oxide (NO) which simply diffuses across the synaptic cleft. The major transmitters and hormones of the gastrointestinal tract are listed in Table 11. Criteria for establishing whether a candidate transmitter functions as a true hormone require that (1) the peptide be released into the circulation in response to a physiologic stimulus and (2) that the target tissue response can be reproduced by infusing the transmitter into the blood, thereby producing the same blood levels that occur physiologically. If an identical target tissue response is elicited, the hormonal effect of the transmitter has been proved. These criteria have been satised for a limited number of gastrointestinal hormones, including gastrin, CCK, secretin, motilin, and glucose-dependent insulinotropic peptide (GIP). Somatostatin is the prototype of a paracrine transmitter. However, depending on its location, somatostatin may also exert endocrine and neural actions. For example, intestinal somatostatin is released into the local circulation following ingestion of fat and acts on the stomach as an enterogastrone to inhibit gastric acid secretion. Some cells release messengers locally and possess cell surface receptors for the same messengers, thus enabling those cells to respond to their own secreted products. This mode of transmission, known as autocrine signaling, has been demonstrated for several growth factors.
Endocrine
Autocrine
Paracrine
Neurocrine
Figure 11 Examples of cell-to-cell communication by chemical transmitters in the gastrointestinal tract. Hormones are secreted from endocrine cells into the blood, where they are carried to distant targets. Paracrine cells secrete transmitters into the paracellular space and act locally. Neurons secrete chemical transmitters or peptides into synapses or onto other cell types. Autocrine transmitters bind to receptors on the cell from which they originate.
This process is known as paracrine signaling and is typical of cells that produce somatostatin.2 Paracrine transmitters are secreted locally and cannot diffuse far. They bind to receptors on nearby cells to exert their biological actions. These actions are limited because they are taken up rapidly by their target cells, destroyed by extracellular enzymes, and adhere to extracellular matrix, all of which limit their ability to act at distant sites. Because paracrine signals act locally, their onset of action is generally rapid and can be terminated abruptly. In contrast, endocrine signaling takes much longer, and termination of signaling requires clearance of hormone from the circulation. A third form of signaling in the gastrointestinal tract is neurotransmission. The enteric nervous system is a complex and sophisticated array of nerve cells and ganglia that is intimately involved in all aspects of gastrointestinal function. When neurons of the gastrointestinal tract are activated, signals in the form of neurotransmitters are released from the nerve terminals. These synapses deliver neurotransmitters to nerves, muscle cells, epithelial and secretory cells, and other specialized cells of the gastrointestinal tract. Neurotransmitters are critical for the processes of digestion and the coordination of gut motility and secretion. Many of the same transmitters are produced by endocrine, paracrine, and neural cells. For instance, cholecystokinin (CCK) is produced by typical endocrine cells of the upper small intestine and is secreted into the bloodstream with ingestion of a meal. However, CCK is also abundant in nerves of the gastrointestinal tract and brain. In neural tissue CCK functions as a neurotransmitter, although, when secreted into the blood, CCK is a classic gastrointestinal hormone. This conservation of transmitters allows the same messenger to have different physiologic actions at different locations and is made possible by the manner in which the transmitter is delivered to its target tissues. Endocrine cells secrete many dif-
NEURAL REGULATION OF THE GASTROINTESTINAL TRACT

The enteric nervous system plays an integral role in the regulation of gut mucosal and motor function.3 It is organized into two major plexuses (Fig. 12). The myenteric plexus lies between the external longitudinal and internal circular muscle layers. The submucosal plexus lies between the circular muscle layer and the mucosa. Although the enteric nervous system receives input from
Chapter 1 Gastrointestinal Hormones and Neurotransmitters

Table 11 Hormones and Transmitters of the Gastrointestinal Tract
Peptides That Act as Growth Factors Epidermal growth factor Fibroblast growth factor Insulin-like factors Nerve growth factor Platelet-derived growth factor Transforming growth factor-b Vascular endothelial growth factor Peptides That Act as Inammatory Mediators Interferons Interleukins Lymphokines Monokines Tumor necrosis factor-a Gut Peptides That Act on Neurons Cholecystokinin Gastrin Motilin Nonpeptide Transmitters Produced in the Gut Acetylcholine Adenosine triphosphate (ATP) Dopamine g-Aminobutyric acid (GABA) Histamine 5-Hydroxytryptamine (5-HT, serotonin) Nitric oxide Norepinephrine Prostaglandins and other eicosanoids Newly Recognized Hormones or Neuropeptides Amylin Ghrelin Guanylin and uroguanylin Leptin
Gut Peptides That Function Mainly as Hormones Gastrin Glucose-dependent insulinotropic peptide (GIP) Glucagon and related gene products (GLP-1, GLP-2, glicentin, oxyntomodulin) Insulin Motilin Pancreatic polypeptide Peptide tyrosine tyrosine (PYY) Secretin Gut Peptides That May Function as Hormones, Neuropeptides, or Paracrine Agents Cholecystokinin (CCK) Corticotropin-releasing factor (CRF) Endothelin Neurotensin Somatostatin Gut Peptides That Act Principally as Neuropeptides Calcitonin gene-related peptide (CGRP) Dynorphin and related gene products Enkephalin and related gene products Galanin Gastrin-releasing peptide (GRP) Neuromedin U Neuropeptide Y Peptide histidine isoleucine (PHI) or peptide histidine methionine (PHM) Pituitary adenylate cyclase-activating peptide (PACAP) Substance P and other tachykinins (neurokinin A, neurokinin B) Thyrotropin-releasing hormone (TRH) Vasoactive intestinal peptide (VIP)
Serosa Circular muscle Submucosa Submucosal plexus Longitudinal muscle Myenteric plexus
Muscularis mucosa Mucosal nerves Mucosa
Figure 12 Organization of the enteric nervous system. The enteric nervous system is composed of two major plexusesone submucosal and one located between the circular and longitudinal smooth muscle layers. These neurons receive and coordinate neural transmission from the gut and central nervous system.
the central and autonomic nervous systems, it can function independently. Nerves of the myenteric plexus project bers primarily to the smooth muscle of the gut, with only a few axons extending to the submucosal plexus. Most of the bers of the submucosal plexus project into the mucosa and the submucosal and myenteric plexuses. Various peptide and nonpeptide neurotransmitters are found in the enteric nervous system. Recent studies using immunohistochemical staining have localized neurotransmitters to specic neurons in the gastrointestinal tract. g-Aminobutyric acid is found primarily in the myenteric plexus and is involved in regulating smooth muscle contraction. Serotonin is found within the plexus and functions as an interneuron transmitter. Adrenergic neurons originate in ganglia of the autonomic nervous system and synapse with enteric neurons. Peptides such as neuropeptide Y (NPY) are often secreted from the same adrenergic neurons and generally exert inhibitory effects such as vasoconstriction.4 Other adrenergic neurons containing somatostatin project to the submucosal plexus, where they inhibit intestinal secretion. Coexistence of peptides and neurotransmitters in the same neurons is not unusual; in fact, the interplay among transmitters is critical for coordinated neural regulation.5 For example, the peptides VIP and peptide histidine

isoleucine (PHI) are commonly found together, as are the tachykinins substance P and substance K, where they have complementary effects. Somatostatin is found in interneurons that project caudally. The inhibitory action of somatostatin is consistent with a role in causing muscle relaxation in advance of a peristaltic wave. The abundance of VIP in the myenteric plexus also suggests that its inhibitory actions are important for smooth muscle relaxation in gut motility. VIP neurons that project from the submucosal plexus to the mucosa most likely stimulate intestinal uid secretion. Other neurons that innervate the mucosa contain acetylcholine. Mucosal cells of the intestine contain receptors for both VIP and acetylcholine, allowing these transmitters to exert synergistic effects, because VIP increases intracellular cyclic adenosine monophosphate (cAMP) levels and acetylcholine increases intracellular calcium in the target cell. Bipolar neurons that project to the mucosa and myenteric plexus act as sensory neurons and often contain substance P, calcitonin gene-related peptide (CGRP), and acetylcholine as neurotransmitters. These neurons participate in pain pathways and modulate inammation. The ability of hormones to act on nerves locally within the submucosa of the intestine and affect more distant sites on nerves such as the vagus expands the potential organs that may be regulated by gut hormones.6 Chemical and mechanical stimuli cause the release of hormones from endocrine cells of the intestinal mucosa. These interactions initiate a wide variety of secretomotor responses, many of which are mediated by enteric neurons. Secretomotor circuits consist of intrinsic primary afferent neurons with nerve endings in the mucosa and extension through the myenteric and submucosal plexuses. This circuitry allows nerves to stimulate mucosal cells to secrete uid and electrolytes and at the same time stimulate muscle contraction. The same motor neurons also have axons that supply arterioles and can initiate vasodilator reexes. Extrinsic primary afferent neurons can be of the vagus, with somal bodies in the nodose ganglia and axons that reach the gut through the vagus nerve, or of the spinal nerves of the thoracic and lumbar regions, whose cell bodies lie in the dorsal root ganglia. Information conducted by extrinsic primary afferent neurons includes pain, heat, and sensations of fullness or emptiness. These neurons are also targets for hormones. For example, the satiety effect of CCK in the bloodstream is mediated through the vagus nerve.7 Specic CCK receptors have been identied on the vagus nerve, and blockade of these receptors abolishes the satiation induced by peripheral CCK. Endocrine, paracrine, and neural transmitters existing within the lamina propria modulate effects on the gut immune system.6 Lymphocytes, macrophages, mast cells, neutrophils, and eosinophils are potential targets for endocrine and neural transmitters and participate in the inammatory cascade. Moreover, inammatory mediators can act directly on enteric nerves. Serotonin released from endocrine cells is involved in intestinal anaphylaxis and stimulates vagal afferent bers that possess the 5-hydroxytryptamine 3 (5-HT3) receptor.
PEPTIDE HORMONES OF THE GASTROINTESTINAL TRACT

SYNTHESIS, POST-TRANSLATIONAL MODIFICATION, AND SECRETION
The expression of peptides is regulated at the level of the gene that resides on dened regions of specic chromosomes. The genes for most of the known gastrointestinal peptides have now been identied. Specic gene regulatory elements determine if and when a protein is produced and the particular cell in which it will be expressed. Gut hormone gene expression is generally linked to peptide production and regulated according to the physiologic needs of the organism. For example, the production of a hormone may increase when gut endocrine cells are stimulated by food, changes in intraluminal pH, exposure to releasing factors, or other transmitters or hormones. These factors may simultaneously stimulate hormone secretion and increase gene expression. Ultimately, hormones are secreted into the circulation, where they are able to bind to receptors on target tissues. Once a biological response is elicited, signals may then be sent back to the endocrine cell to turn off hormone secretion. This negative feedback mechanism is common to many physiologic systems and avoids excess production and secretion of hormone. All gastrointestinal peptides are synthesized via gene transcription of DNA into messenger RNA (mRNA) and subsequent translation of mRNA into precursor proteins known as preprohormones. Peptides that are to be secreted contain a signal sequence that directs the newly translated protein to the endoplasmic reticulum, where the signal sequence is cleaved and the prepropeptide product is prepared for structural modications.8 These precursors undergo intracellular processing and are transported to the Golgi apparatus and packaged in secretory granules. Further modications in peptide structure may occur within the Golgi apparatus (e.g., sulfation) that is important for the bioactivity of many peptide hormones such as CCK. Secretory granules may be targeted for immediate release or stored in close proximity to the plasma membrane for release following appropriate cell stimulation. When gastrointestinal endocrine cells are stimulated, mature hormone is secreted into the paracellular space and is taken up into the bloodstream. For many hormones, such as gastrin and CCK, multiple molecular forms exist in blood and tissues. Although there is only a single gene for these peptides, the different molecular forms result from differences in pretranslational or posttranslational processing (Fig. 13). A common mechanism of pretranslational processing includes alternative splicing of mRNA, which generates unique peptides from the same gene. Post-translational changes include cleavage of precursor molecules. Enzymatic cleavage of the signal peptide produces a prohormone. Other post-translational features that result in mature gastrointestinal peptides include peptide cleavage to smaller forms (e.g., somatostatin), amidation of the carboxyl terminus (e.g., gastrin), and sulfation of tyrosine residues (e.g., CCK). These processing steps are

intron Gene 5 Exon 1 Exon 2 transcription mRNA Cap site translation Prepro-peptide Signal spacer peptide Post-translational processing Pro-peptide poly A intron Exon 3 3
Peptide-AB
Peptide-A
Figure 13 Schematic representation of the production of gastrointestinal peptides. The genetic information is transcribed into mRNA, which is translated to a prepropeptide. Subsequent enzymatic cleavage produces peptides of various lengths.
usually critical for biological activity of the hormone. For example, sulfated CCK is 100-fold more potent than its unsulfated form. The vast biochemical complexity of gastroenteropancreatic hormones is evident in the different tissues that secrete these peptides. As gastrointestinal peptides are secreted from endocrine as well as nervous tissue, the distinct tissue involved often determines the processing steps for production of the peptide. Many hormone genes are capable of manufacturing alternatively spliced mRNAs or proteins that undergo different post-translational processing and ultimately produce hormones of different sizes. These modications are important for receptor binding, signal transduction, and consequent cellular responses.9 Recently, it has become possible to express human genes in other species. By introducing specic hormoneproducing genes into pigs or sheep, human hormones have been produced for medicinal use.10 With the rapid sequencing of the human genome, it is likely that novel methods of gene expression will expand the therapeutic use of human proteins. Drugs are being developed that inhibit the transcription of DNA into mRNA or that block the gene elements responsible for turning on specic hormone production (e.g., antisense oligonucleotides).11 This technology is based on the principle that nucleotide sequences bind to critical DNA regions and prevent transcription into mRNA. Similarly, oligonucleotides can be made to interact with mRNA and alter (or inhibit) translation of a protein product. These principles may be applicable to the treatment of the growing list of diseases that result from aberrant protein processing.12,13
GASTRIN
As discussed in more detail in Chapter 47, gastrin is the major hormone that stimulates gastric acid secretion.
Subsequently, gastrin was found to have growthpromoting effects on gastric mucosa and possibly on some cancers.14 Human gastrin is the product of a single gene located on chromosome 17. The active hormone is generated from a precursor peptide called preprogastrin. Human preprogastrin contains 101 amino acids (AAs), including a signal peptide (21 AA), spacer sequence (37 AA), gastrin component (34 AA), and a 9-AA extension at the carboxyl terminus. The enzymatic processing of preprogastrin produces all the known physiologically active forms of gastrin. Preprogastrin is processed into progastrin and gastrin peptide fragments of various sizes by sequential enzymatic cleavage. The two major forms of gastrin are G34 and G17, although smaller forms exist. The common feature of all gastrins is an amidated tetrapeptide (TryMet-Asp-Phe-NH2) carboxyl terminus, which imparts full biological activity. Modication by sulfation at tyrosine residues produces alternative gastrin forms of equal biological potency. Most gastrin is produced in endocrine cells of the gastric antrum.15 Much smaller amounts of gastrin are produced in other regions of the gastrointestinal tract, including the proximal stomach, duodenum, jejunum, ileum, and pancreas. Gastrin has also been found outside the gastrointestinal tract, including in the brain, adrenal gland, respiratory tract, and reproductive organs, although its biological role in these sites is unknown. The receptors for gastrin and CCK are related and constitute the so-called gastrin/CCK receptor family. The CCK-1 and CCK-2 (previously known as CCK-A and -B) receptor complementary DNAs were cloned from pancreas and brain, respectively, after which it was recognized that the CCK-2 receptor was identical to the gastrin receptor of the stomach.16 The CCK-1 receptor is present in the gallbladder and, in most species, in the pancreas and has a 1000-fold higher afnity for CCK than for gastrin. The CCK-1 and the CCK-2/gastrin receptors have greater than 50% sequence homology and respond differentially to various receptor antagonists and to gastrin. Gastrin is released from specialized endocrine cells (G cells) into the circulation in response to a meal. The specic components of a meal that stimulate gastrin release include protein, peptides, and amino acids. Gastrin release is profoundly inuenced by the pH of the stomach. Fasting and increased gastric acidity inhibit gastrin release, whereas a high gastric pH is a strong stimulus for its secretion. Hypergastrinemia occurs in pathological states that are associated with decreased acid production, such as atrophic gastritis. Serum gastrin levels can also become elevated in patients on prolonged acid-suppressive medications, such as histamine receptor antagonists and proton pump inhibitors. Hypergastrinemia in these conditions is due to stimulation of gastrin production by the alkaline pH environment. Another important, but far less common, cause of hypergastrinemia is a gastrin-producing tumor, also known as Zollinger-Ellison syndrome (see Chapter 31). The gastrin analog, pentagastrin, has been used clinically to stimulate histamine and gastric acid

secretion in diagnostic tests of acid secretory capacity (see Chapter 47). Secretin also inhibits gastric acid secretion and intestinal motility. Human secretin is a 27 amino acid peptide and, similar to many other gastrointestinal peptides, is amidated at the carboxyl terminus. It is the founding member of the secretin/glucagon/VIP family of structurally related gastrointestinal hormones. Secretin is selectively expressed in specialized enteroendocrine cells of the small intestine called S cells.24 The secretin receptor is a member of a large family of G protein-coupled receptors (GPCRs) that is structurally similar to receptors for glucagon, calcitonin, parathyroid hormone, pituitary adenylate cyclase-activating peptide (PACAP), and vasoactive intestinal polypeptide (VIP). One of the major physiologic actions of secretin is stimulation of pancreatic uid and bicarbonate secretion (see Chapter 54). Pancreatic bicarbonate, on reaching the duodenum, neutralizes gastric acid and raises the duodenal pH, thereby turning off secretin release (negative feedback). It has been suggested that acid-stimulated secretin release is regulated by an endogenous intestinal secretin-releasing factor.25 This peptide may stimulate secretin release from S cells until the ow of pancreatic proteases is sufcient to degrade the releasing factor and terminate secretin release. Although the primary action of secretin is to produce pancreatic uid and bicarbonate secretion, it is also an enterogastrone, a substance that is released when fat is present in the gastrointestinal lumen and that inhibits gastric acid secretion. In physiologic concentrations, secretin inhibits gastrin release, gastric acid secretion, and gastric motility.26 The most common clinical application of secretin is in the diagnosis of gastrin-secreting tumors,27 as discussed in Chapter 31.
CHOLECYSTOKININ
Cholecystokinin is a peptide transmitter produced by I cells of the small intestine and is secreted into the blood following ingestion of a meal. Circulating CCK binds to specic CCK-1 receptors on the gallbladder, pancreas, smooth muscle of the stomach, and peripheral nerves to stimulate gallbladder contraction and pancreatic secretion, regulate gastric emptying and bowel motility, and induce satiety.17 These effects serve to coordinate the ingestion, digestion, and absorption of dietary nutrients. Ingested fat and protein are the major food components that stimulate CCK release. CCK was originally identied as a 33 amino acid peptide. However, since its discovery larger and smaller forms of CCK have been isolated from blood, intestine, and brain. All forms of CCK are produced from a single gene by post-translational processing of a preprohormone. Forms of CCK ranging in size from CCK-58 to CCK-8 have similar biological activities.18 CCK is the major hormonal regulator of gallbladder contraction. It also plays an important role in regulating meal-stimulated pancreatic secretion (see Chapters 54 and 60). In many species this latter effect is mediated directly through receptors on pancreatic acinar cells, but in humans, where pancreatic CCK-1 receptors are less abundant, CCK appears to stimulate pancreatic secretion indirectly through enteropancreatic neurons that possess CCK-1 receptors. In some species CCK has trophic effects on the pancreas, although its potential role in human pancreatic neoplasia is speculative. CCK also has been shown to delay gastric emptying.19 This action may be important in coordinating the delivery of food from the stomach to the intestine. CCK has been proposed as a major mediator of satiety and food intake, an effect that is particularly noticeable when food is in the stomach or intestine. Clinically, CCK has been used with secretin to stimulate pancreatic secretion for pancreatic function testing. It is also used radiographically or scintigraphically to evaluate gallbladder contractility. There are no known diseases of CCK excess. Low CCK levels have been reported in individuals with celiac disease who have reduced intestinal mucosal surface area and in cases of bulimia nervosa.20,21 Elevated levels of CCK have been reported in some patients with chronic pancreatitis, presumably owing to reduced pancreatic enzyme secretion and interruption of negative feedback regulation of CCK release.22
VASOACTIVE INTESTINAL POLYPEPTIDE

Vasoactive intestinal polypeptide (VIP) is a neuromodulator that has broad signicance in intestinal physiology. VIP is a potent vasodilator, causes smooth muscle relaxation, and stimulates epithelial cell secretion.28,29 As a chemical messenger, VIP is released from nerve terminals and acts locally on cells bearing VIP receptors. VIP belongs to a family of structurally related gastrointestinal peptides that includes secretin and glucagon. The VIP receptor is a G protein-coupled receptor that stimulates intracellular cyclic AMP generation. Like other gastrointestinal peptides, VIP is synthesized as a precursor molecule that is cleaved to an active peptide of 28 amino acids. VIP is expressed primarily in neurons of the peripheral/enteric and central nervous systems and is released along with other peptides, including primarily PHI and/or peptide histidine methionine (see Table 11).30 VIP is an important neurotransmitter throughout the central and peripheral nervous systems.31 Because of its wide distribution, VIP has effects on many organ systems, although most notably in the gastrointestinal tract; VIP stimulates uid and electrolyte secretion from intestinal epithelium and bile duct cholangiocytes.32,33
SECRETIN
The rst hormone, secretin, was discovered when it was observed that intestinal extracts, when injected intravenously into dogs, caused pancreatic secretion.23 Secretin is released by acid in the duodenum and stimulates pancreatic uid and bicarbonate secretion, leading to neutralization of acidic chyme in the intestine.

VIP, along with NO, is a primary component of nonadrenergic, noncholinergic nerve transmission in the gut.34 Gastrointestinal smooth muscle exhibits a basal tone, or sustained tension, due to rhythmic depolarizations of the smooth muscle membrane potential. VIP serves as an inhibitory transmitter of this rhythmic activity, causing membrane hyperpolarization and subsequent relaxation of gastrointestinal smooth muscle. Accordingly, VIP is an important neuromodulator of sphincters of the gastrointestinal tract, including the lower esophageal sphincter and sphincter of Oddi. In certain pathologic conditions, such as achalasia and Hirschsprungs disease, the lack of VIP innervation is believed to play a major role in defective esophageal relaxation and bowel dysmotility, respectively.35,36 Unlike gastrointestinal endocrine cells that line the mucosa of the gut, VIP is produced and released from neurons and it is likely that most measurable VIP in serum is of neuronal origin. Normally, serum VIP levels are low and do not appreciably change with a meal. However, in pancreatic cholera, also known as watery diarrhea-hypokalemia-achlorhydria (WDHA) or VernerMorrison syndrome,37 VIP levels can be extraordinarily high.32 VIP-secreting tumors usually produce a voluminous diarrhea,38 as discussed in Chapter 31. tal muscle and the liver to exert its gluco-regulatory effects. GLP-1 stimulates insulin secretion and augments the effects of glucose on the pancreatic beta cell (see Entero-insular Axis). GLP-1 analogs are being developed for the treatment of type II diabetes mellitus. GLP-2 is an intestinal growth factor that may have therapeutic implications in the maintenance of the gastrointestinal mucosal mass and the reversal of villus atrophy.
GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE

Glucose-dependent insulinotropic polypeptide (GIP) was discovered based on its ability to inhibit gastric acid secretion (enterogastrone effect) and was originally named gastric inhibitory polypeptide. It was subsequently shown that the effects on gastric acid secretion occur only at very high concentrations that are outside the physiologic range. However, GIP has potent effects on insulin release that (like GLP-1) potentiates glucose-stimulated insulin secretion.41 Based on this action, GIP was redened as glucose-dependent insulinotropic polypeptide. GIP is a 42 amino acid peptide that is produced by K cells residing in the mucosa of the small intestine. GIP is released into the blood after ingestion of glucose or fat. In the presence of elevated blood glucose levels, GIP binds to its receptor on beta cells activating adenylate cyclase and other pathways that increase intracellular calcium concentrations leading to insulin secretion. Importantly, however, the effects on insulin secretion occur only if hyperglycemia exists; GIP does not stimulate insulin release under fasting conditions. GIP receptors are also expressed on adipocytes through which GIP augments triglyceride storage that may contribute to fat accumulation. Based on the insulinotropic properties of GIP coupled with its effects on adipocytes, it has been proposed that GIP may play a role in obesity and development of insulin resistance associated with type II diabetes mellitus.42 Consistent with this proposal was the recent experimental nding that mice lacking the GIP receptor did not gain weight when placed on a high fat diet.43 It remains to be seen whether GIP antagonists can be used to treat obesity. In rare circumstances, receptors for GIP may be aberrantly expressed in the adrenal cortex, resulting in food-dependent Cushings syndrome.43a,43b
GLUCAGON
Glucagon is synthesized and released from pancreatic alpha cells and from cells of the ileum and colon (L cells). Pancreatic glucagon is a 29 amino acid peptide that regulates glucose homeostasis via gluconeogenesis, glycogenolysis, and lipolysis and is counter-regulatory to insulin. The gene for glucagon encodes not only preproglucagon but also glucagon-like peptides (GLPs). This precursor peptide consists of a signal peptide, a glucagon-related polypeptide, glucagon, and GLP-1 and GLP-2. Tissue-specic peptide processing occurs through prohormone convertases that produce glucagon in the pancreas and GLP-1 and GLP-2 in the intestine39 (Fig. 14). Glucagon and GLP-1 regulate glucose homeostasis.40 Glucagon is released from the pancreas in response to a meal and binds to G protein-coupled receptors on skele-
Proglucagon
Glucagon
GLP-1
GLP-2
PANCREATIC POLYPEPTIDE FAMILY

Originally isolated during the preparation of insulin, pancreatic polypeptide (PP) is the founding member of the PP family.44 The PP family of peptides includes neuropeptide Y (NPY) and peptide tyrosine tyrosine (PYY), which were discovered owing to the presence of a Cterminal tyrosine amide.45,46 PP is stored and secreted from specialized pancreatic endocrine cells (PP cells),47 whereas NPY is a principal neurotransmitter found in the central and peripheral nervous systems.48 PYY has been localized to enteroendocrine cells throughout the gastrointestinal tract but is found in greatest concentrations in the ileum and colon.49
Pancreas
Small intestine
Glucagon
GLP-1
GLP-2
Figure 14 Different post-translational processing of glucagon in the pancreas and small intestine. The glucagon gene transcript is transcribed and translated into a prohormone (shown here as proglucagon) capable of producing glucagon, glucagon-like peptide-1 (GLP-1), and GLP-2. However, only glucagon is produced in the pancreas owing to specic processing. In the small intestine, GLP-1 and GLP-2 are the primary products.
10

The PP/PYY/NPY family of peptides functions as endocrine, paracrine, and neurocrine transmitters in the regulation of a number of functions that result from activation of one of ve receptor subtypes.50 PP inhibits pancreatic exocrine secretion, gallbladder contraction, and gut motility.51 PYY inhibits vagally stimulated gastric acid secretion and other motor and secretory functions.52 Recently, an abbreviated form of PYY lacking the rst two amino acids of the normally produced 36 amino acid peptide, PYY3-36, was shown to reduce food intake when administered to humans, indicating that intestinally released peptide may play a role in regulating meal size.53 NPY is one of the most abundant peptides in the central nervous system and, in contrast to PYY3-36, is a potent stimulant of food intake.54 Peripherally, NPY affects vascular and gastrointestinal smooth muscle function.55 cells are open to the lumen where they are directly exposed to acid. Low gastric pH stimulates D cells that lie in close proximity to gastrin-producing cells to secrete somatostatin and inhibit gastrin release (see Chapter 47). Reduced gastrin secretion decreases the stimulus for acid production and the pH of the stomach contents rises. Thus, some of the inhibitory effects of gastric acid on gastrin release (see Gastrin) are mediated by somatostatin. Somatostatin release is also inuenced by mechanical stimulation; dietary components of a meal including protein, fat, and glucose; as well as other hormones and neurotransmitters.63 Muscarinic stimulation appears to be the most important neural stimulus to somatostatin secretion. At least ve somatostatin receptors have been identied that account for divergent pharmacologic properties.64 For example, receptor subtypes 2 and 3 couple to inhibitory G proteins but receptor subtype 1 does not. In addition, only somatostatin receptor subtype 3 inhibits adenylate cyclase. The inhibitory effects of somatostatin are mediated by either a decrease in cyclic AMP, Ca2+ channel inhibition, or K+ channel opening. In the gut, somatostatin has broad inhibitory actions. In addition to effects on gastric acid, somatostatin reduces pepsinogen secretion. Somatostatin profoundly inhibits pancreatic enzyme, uid and bicarbonate secretion, and it reduces bile ow.65 The effects of somatostatin on gut motility are largely inhibitory with the exception that it stimulates the migrating motor complex, possibly through effects on motilin. Somatostatin also reduces intestinal transport of nutrients and uid, reduces splanchnic blood ow, and has inhibitory effects on tissue growth and proliferation.66 Because of its varied physiologic effects, somatostatin has several clinically important pharmacologic uses. Many endocrine cells possess somatostatin receptors and are sensitive to inhibitory regulation. Therefore, somatostatin and more recently developed somatostatin analogs are used to treat conditions of hormone excess produced by endocrine tumorsincluding acromegaly, carcinoid tumors, and islet cell tumors (including gastrinomas).67 Its ability to reduce splanchnic blood ow and portal venous pressure led to somatostatin analogs being useful in treating esophageal variceal bleeding.68 The inhibitory effects on secretion have been exploited by using somatostatin analogs to treat some forms of diarrhea and reduce uid output from pancreatic stulae. Many endocrine tumors express abundant somatostatin receptors, making it possible to use radiolabeled somatostatin analogs, such as octreotide, to localize even small tumors throughout the body.
SUBSTANCE P AND THE TACHYKININS

Substance P belongs to the tachykinin family of peptides, which includes substance P, neurokinin A, and neurokinin B. The tachykinins are found throughout the peripheral and central nervous systems, and are important mediators of neuropathic inammation.56 Tachykinins, as a group, are encoded by two genes that produce preprotachykinin A and preprotachykinin B. Common to both is a well-conserved C-terminal pentapeptide. Transcriptional and translational processing produce substance P, neurokinin A, and/or neurokinin B, which are regulated in large part by alternative splicing. These peptides function primarily as neuropeptides. Substance P is a neurotransmitter of primary sensory afferent neurons and binds to specic receptors in lamina I of the spinal cord.57 Three receptors for this family of peptides have been identied (NK-1, NK-2, and NK-3).58 Substance P is the primary ligand for the NK-1 receptor, neurokinin A for the NK-2, and neurokinin B for the NK-3. However, all peptides can bind and signal through all three receptor subtypes. Substance P has been implicated as a primary mediator of neurogenic inammation. In the intestine, Clostridium difcileinitiated experimental colitis results from toxininduced release of substance P and consequent activation of the NK-1 receptor.59 These inammatory sequelae can be blocked by substance P receptor antagonists. Substance P receptors are more abundant in the intestine of patients with ulcerative colitis and Crohns disease.60
SOMATOSTATIN
Somatostatin is a 14 amino acid cyclic peptide that was initially identied as an inhibitor of growth hormone secretion. Since its discovery, it has been found in virtually every organ in the body and throughout the gastrointestinal tract. In the gut, somatostatin is produced by D cells in the gastric and intestinal mucosa and islets of the pancreas as well as enteric neurons.61 Somatostatin has a number of pharmacologic effects that are mostly inhibitory. In the stomach, somatostatin plays an important role in regulating gastric acid secretion.62 In the antrum, D
MOTILIN
Motilin is a 22 amino acid peptide produced by endocrine cells of the duodenal epithelium.69 Motilin is secreted into the blood in a periodic and recurrent pattern that is synchronized with the migrating motor complex (MMC) under fasting conditions. Elevations in blood motilin levels regulate the phase III contractions that initiate in the antroduodenal region and progress toward

the distal gut. Motilin secretion is not stimulated by eating. Motilin binds to specic receptors on smooth muscle cells of the esophagus, stomach, and small and large intestines through which it exerts propulsive activity.70 Agonists to the motilin receptor such as erythromycin have pronounced effects on gastrointestinal motility, which occasionally produces undesired side effects of abdominal cramping and diarrhea.71 However, motilin agonists may be useful to treat conditions of impaired gastric and intestinal motility.72 negative energy balance such as starvation or anorexia. In contrast, ghrelin levels are low after eating and in obesity. Ghrelin appears to play a central role in the neurohormonal regulation of food intake and energy homeostasis. The gastric fundus is the most abundant source of ghrelin, although smaller amounts are found in the intestine, pancreas, pituitary, kidney, and placenta. Ghrelin is produced by distinctive endocrine cells known as P/D1 cells86,87 that are of two types, open and closed. The open type is exposed to the lumen of the stomach where it comes into contact with gastric contents, whereas the closed type is not open to the lumen of the stomach, but rather lies in close proximity to the capillary network of the lamina propria.88 Both cell types secrete hormone into the bloodstream. Based on its structure, it is a member of the motilin family of peptides and, like motilin, ghrelin stimulates gastric contraction and enhances stomach emptying. The observations that circulating ghrelin levels increase sharply before a meal and fall abruptly after a meal suggest that ghrelin serves as a signal for initiation of feeding. The effects of food on plasma ghrelin levels can be reproduced by ingestion of glucose and appear to be unrelated to the physical effects of a meal on gastric distention. Circulating ghrelin levels are low in states of positive energy balance such as obesity and are inversely correlated with body mass index.89,90 Conversely, ghrelin levels are high in fasting, cachexia, and anorexia. Importantly, weight loss increases circulating ghrelin levels.91 Ghrelin released from the stomach acts on the vagus nerve to exert its effects on feeding. However, it is also active when delivered to the central nervous system; in this location ghrelin activates NPY and agouti-related protein-producing neurons in the arcuate nucleus of the hypothalamus, which are involved in the regulation of feeding.85,92 Gastric bypass patients do not demonstrate the premeal increase in plasma ghrelin that is seen in normal individuals.93 This lack of ghrelin response may be one of the mechanisms contributing to the overall effectiveness of gastric bypass surgery. Prader-Willi syndrome is a genetic obesity syndrome that is characterized by severe hyperphagia, growth hormone deciency, mental retardation, and hypogonadism. Although obesity is ordinarily associated with low ghrelin levels, patients with Prader-Willi syndrome have high circulating ghrelin levels that do not decline after a meal.94,95 The levels of ghrelin in this syndrome are similar to those that can stimulate appetite and increase food intake in individuals receiving infusions of exogenous ghrelinsuggesting that abnormal ghrelin secretion may be responsible for the hyperphagia in Prader-Willi syndrome.96
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LEPTIN
Leptin is a 167 amino acid protein that is secreted primarily from adipocytes and blood levels reect total body fat stores.73 Its primary action appears to be to reduce food intake. Leptin is a member of the cytokine family of signaling molecules. Five different forms of leptin receptors have been reported.74 A short form of the receptor appears to transport leptin from the blood across the blood-brain barrier where it has access to the hypothalamus. A long form of the leptin receptor is located in hypothalamic nuclei where leptin binds and activates the janus kinase signal transduction and translation system (JAK STAT).75 Small amounts of leptin are produced by the chief cells of the stomach and by the placenta, and are present in breast milk. Peripheral administration of leptin reduces food intake. However, this effect is reduced as animals become obese. Interestingly, when injected into the central nervous system, obese animals respond normally to leptin, indicating that leptin resistance occurs at the level of the leptin receptor that transports leptin across the bloodbrain barrier.76 Leptins ability to reduce food intake occurs within the brain by decreasing neuropeptide Y (NPY) (a potent stimulant of food intake) and increasing a-melanocyte stimulating hormone (an inhibitor of food intake).77 Peripherally, leptin acts synergistically with cholecystokinin to reduce meal size.78 Blood levels of leptin increase as obesity develops and leptin appears to reect total fat content.79 At the cellular level, large adipocytes produce more leptin than do small adipocytes. Because of its effects on food intake, it was initially thought that exogenous leptin could be used therapeutically to treat obesity. However, only a very modest effect on weight loss has been demonstrated in clinical trials. Leptin deciency has been reported as a cause of obesity in a few families, but this condition is extremely rare.80,81 One family with morbid obesity has been found to have a mutation in the leptin receptor.82
GHRELIN
Ghrelin is a 28 amino acid peptide produced by the stomach and is the natural ligand for the growth hormone secretagogue (GHS) receptor.83 When administered centrally or peripherally, ghrelin stimulates growth hormone secretion, increases food intake, and produces weight gain.84,85 Circulating ghrelin levels increase during periods of fasting or under conditions associated with
OTHER CHEMICAL MESSENGERS OF THE GASTROINTESTINAL TRACT

The enteric nervous system, through intrinsic and extrinsic neural circuits, controls gastrointestinal function. This control is mediated by a variety of chemical messengers, including motor and sensory pathways of the sym-
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pathetic and parasympathetic nervous systems. The parasympathetic preganglionic input is provided by cholinergic neurons and elicits excitatory effects on gastrointestinal motility via nicotinic and muscarinic receptors. Sympathetic input occurs through postganglionic adrenergic neurons. system, dopamine regulates food intake, emotions, and endocrine responses, and peripherally, it controls hormone secretion, vascular tone, and gastrointestinal motility. Characterization of dopamine in the gastrointestinal tract has been challenging for several reasons. First, dopamine can produce inhibitory and excitatory effects on gastrointestinal motility.98 Generally, the excitatory response, which is mediated by presynaptic receptors, occurs at a lower agonist concentration than the inhibitory effect that is mediated by postsynaptic receptors. Second, localization of dopamine receptors has been hampered by identication of dopamine receptors in locations that appear to be species specic.99 Third, studies of dopamine in gastrointestinal tract motility have often used pharmacologic amounts of this agonist. Therefore, interpretation of results has been confounded by the ability of dopamine to activate adrenergic receptors at high doses. Classically, dopamine was thought to act via two distinct receptor subtypes: type 1 and type 2. Molecular cloning has now demonstrated ve dopamine receptor subtypes, each with a unique gene locus and molecular structure.99 Dopamine receptors are integral membrane G-protein coupled receptors (GPCRs), and each receptor subtype has a specic pharmacologic prole when exposed to agonists and antagonists. After release from the nerve terminal, dopamine is cleared from the synaptic cleft by a specic dopamine transporter.
ACETYLCHOLINE
Acetylcholine is synthesized in cholinergic neurons and is the principal regulator of gastrointestinal motility as well as pancreatic secretion. Acetylcholine is stored in nerve terminals and is released by nerve depolarization. Released acetylcholine binds to postsynaptic muscarinic and/or nicotinic receptors. Nicotinic acetylcholine receptors belong to a family of ligand-gated ion channels and are homopentamers or heteropentamers composed of a, b, g, d, and e subunits.97 The a subunit is believed to be the mediator of postsynaptic membrane depolarization following acetylcholine receptor binding. Muscarinic receptors belong to the heptahelical GPCR family. There are ve known muscarinic cholinergic receptors (M1 to M5). Muscarinic receptors can be further classied based on receptor signal transduction, with M1, M3, and M5 stimulating adenylate cyclase and M2 and M4 inhibiting this enzyme. Acetylcholine is degraded by the enzyme acetylcholinesterase, and the products may be recycled through high-afnity transporters on the nerve terminal.
SEROTONIN CATECHOLAMINES
The primary catecholamine neurotransmitters of the enteric nervous system include norepinephrine and dopamine. Norepinephrine is synthesized from tyrosine and released from postganglionic sympathetic nerve terminals that innervate enteric ganglia and blood vessels. Tyrosine is converted to dopa by tyrosine hydroxylase. Dopa is initially converted into dopamine by dopa decarboxylase and packaged into secretory granules. Norepinephrine is formed from dopamine by the action of dopamine b-hydroxylase within the secretory granule. After an appropriate stimulus, norepinephrinecontaining secretory granules are released from nerve terminals and bind to adrenergic receptors. Adrenergic receptors are G protein-coupled, have seven typical membrane-spanning domains, and are of two basic types: a and b. a-Adrenergic receptors are further classied into a1A, a1B, a2A, a2B, a2C, and a2D. Similarly, b receptors include b1, b2, and b3. Adrenergic receptors are known to signal through a variety of G proteins, resulting in stimulation or inhibition of adenylate cyclase and other effector systems. Norepinephrine signaling is terminated by intracellular monoamine oxidase or by rapid reuptake by an amine transporter. The actions of adrenergic receptor stimulation regulate smooth muscle contraction, intestinal blood ow, and gastrointestinal secretion. Dopamine is an important mediator of gastrointestinal secretion, absorption, and motility and is the predominant catecholamine neurotransmitter of the central and peripheral nervous systems. In the central nervous Serotonin has long been known to play a role in gastrointestinal neurotransmission.100 The gastrointestinal tract contains more than 95% of the total body serotonin, and serotonin is important in a variety of processes, including epithelial secretion, bowel motility, nausea and emesis.101 Serotonin is synthesized from tryptophan, an essential amino acid, and is converted to its active form in nerve terminals. Secreted serotonin is inactivated in the synaptic cleft by reuptake via a serotonin-specic transporter or metabolized by monoamine oxidase and other enzymes to 5-hydroxyindoleacetic acid (5-HIAA). Most plasma serotonin is derived from the gut, where it is found in mucosal enterochromafn cells and the enteric nervous system. Serotonin mediates its effects by binding to a specic receptor. There are seven different serotonin receptor subtypes found on enteric neurons, enterochromafn cells, and gastrointestinal smooth muscle (5-HT1 to 5-HT7). The actions of serotonin are complex (Fig. 15).102 It can cause smooth muscle contraction through stimulation of cholinergic nerves or relaxation by stimulating inhibitory nitric oxide-containing neurons.101 Serotonin released from mucosal cells stimulates sensory neurons, initiating a peristaltic reex and secretion via 5-HT4 receptors and modulates sensation through activation of 5-HT3 receptors.100 The myenteric plexus contains serotoninergic interneurons that project to the submucosal plexus as well as ganglia extrinsic to the bowel wall. Extrinsic neurons activated by serotonin participate in bowel sensation and may be responsible for abdominal pain, nausea, and symptoms associated with irritable
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CNS
Longitudinal muscle
5HT3 Myenteric plexus Excitatory motor neuron 5HT4 5HT4 Inhibitory motor neuron 5HT3
Circular muscle
5HT3 Intrinsic primary afferent neuron Sensory neuron 5HT4 5HT3
Extrinsic afferent neuron
Submucosal plexus
5HT3 Mucosa
Enterochromaffin cells
Figure 15 Role of serotonin in the enteric nervous system. This model illustrates the location of 5HT3 and 5HT4 receptor subtypes in the gut. (Modied from Talley NJ: Serotoninergic neuroenteric modulators. Lancet 358:2061, 2001).
bowel syndrome. Intrinsic neurons activated by serotonin are primary components of the peristaltic and secretory reexes responsible for normal gastrointestinal function. Serotonin may also activate vagal afferent pathways and, in the central nervous system, it modulates appetite, mood, and sexual function. Serotonin, and its receptor, have been implicated in the pathogenesis of motility disorders of the gastrointestinal tract.103 Characterization of specic serotonin receptor subtypes has led to the development of selective agonists and antagonists for the treatment of irritable bowel syndrome and chronic constipation and diarrhea. For example, 5-HT3 receptor antagonists which reduce intestinal secretion are used to treat diarrhea-predominant irritable bowel syndrome. 5-HT4 receptor agonists elicit prokinetic effects and are used to treat constipationpredominant irritable bowel syndrome and other motility disorders.104,105 Serotonin can also be enzymatically converted to melatonin by serotonin N-acetyltransferase.105a Other than the pineal gland, the gastrointestinal tract is the major source of the bodys melatonin. Melatonin is produced in enterochromafn cells and is released into the blood after ingestion of a meal. A number of actions on the gastrointestinal tract have been described for
melatonin including reducing gastric acid and pepsin secretion, inducing smooth muscle relaxation, and preventing epithelial injury through an antioxidant effect.105b
HISTAMINE
In the gastrointestinal tract, histamine is best known for its central role in regulating gastric acid secretion (see Chapter 47) and intestinal motility. Histamine is produced by enterochromafn-like cells of the stomach and intestine as well as enteric nerves. Histamine is synthesized from L-histidine by histidine decarboxylase and activates three GPCR subtypes. H1 receptors are found on smooth muscle and vascular endothelial cells and are linked to phospholipase C (PLC) activation. As such, the H1 receptor mediates many of the allergic responses induced by histamine. H2 receptors are present on gastric parietal cells, smooth muscle, and cardiac myocytes. H2 receptor binding stimulates Gs and activates adenylate cyclase. H3 receptors are present in the central nervous system and on gastrointestinal tract enterochromafn cells. These H3 receptors signal through Gi and inhibit
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adenylate cyclase.106 Histamine can also interact with the N-methyl-D-aspartate (NMDA) receptor and enhance activity of NMDA-bearing neurons independent of the three known histamine receptor subtypes. Unlike other neurotransmitters, there is no known transporter responsible for termination of histamines action. However, histamine is metabolized to telemethylhistamine by histamine N-methyltransferase and is then degraded to telemethylimidazoleacetic acid by monoamine oxidase B and an aldehyde dehydrogenase.
CYTOKINES
Cytokines are a group of polypeptides produced by a variety of immunomodulatory cells and are involved in cell proliferation, immunity, and inammation (see Chapter 2). Cytokines are induced by specic stimuli, such as toxins produced by pathogens, and often elicit a complex response involving a variety of other cellular mediators to eradicate the foreign substance. Cytokines may be categorized as interleukins (ILs), tumor necrosis factors (TNFs), lymphotoxins, interferons, colony-stimulating factors (CSFs), and others.111 Interleukins can be further subtyped into at least 29 separate substances: IL1 to IL-29. There are two TNFs: TNF-a and TNF-b, which are also known as lymphotoxin-a. Interferons are produced during viral or bacterial infection and come in two varieties: interferon-a (also known as leukocyte-derived interferon or interferon-b) and interferon-g. Interferon-a is produced by T lymphocytes and is used clinically in the treatment of viral hepatitis (see Chapters 75 and 76). The major CSFs are granulocyte/mononuclear phagocyteCSF, mononuclear phagocyte-CSF, and granulocyte-CSF. These agents are used in chemotherapy-induced neutropenia and marrow support after bone marrow transplantation. Chemokines initiate and propagate inammation and are of two groups: CXC (a chemokines) and CC (b chemokines). Other cytokines, such as transforming growth factor (TGF)-b and platelet-derived growth factor (PDGF), have proliferative effects.
NITRIC OXIDE
Nitric oxide (NO) is a unique chemical messenger produced from L-arginine by the enzyme nitric oxide synthase (NOS).107 Three types of NOS are known. Types I and III are also known as endothelial NOS and neuronal NOS, respectively, and are constitutively active. Small changes in their NOS activities can occur through elevations in intracellular calcium. The inducible form of NOS (type II) is apparent only when cells become activated by specic inammatory cytokines. This form of NOS is capable of producing large amounts of NO and is calcium independent. NOS is often colocalized with VIP and PACAP in neurons of the enteric nervous system.108 NO, being an unstable gas, has a relatively short halflife. Unlike most neurotransmitters and hormones, NO does not act via a membrane-bound receptor. Instead, NO readily diffuses into adjacent target cells to directly activate guanylate cyclase (Fig. 16). NO activity is terminated by oxidation to nitrate and nitrite. Many enteric nerves use NO to signal neighboring cells and induce epithelial secretion, vasodilation, or muscle relaxation. NO is also produced by macrophages and neutrophils to help kill invading organisms.109
SIGNAL TRANSDUCTION
Cells live in a constantly changing milieu. The structure and biochemical nature of this environment are dynamic, and for cells to function normally they must be able to access this changing information. The biochemical mediators of this information are cell surface receptors and transmitters. Receptors transduce signals from the extracellular space to the intracellular compartment. Each step in the process from receptor activation to receptor desensitization, internalization, and resensitization represents a potential regulatory checkpoint and possible target for therapeutic intervention. Cell surface receptors include GPCRs, as well as ion channels and enzymelinked receptors.
ADENOSINE
Adenosine is an endogenous nucleoside that acts through any of four GPCR subtypes.110 Adenosine causes relaxation of intestinal smooth muscle and stimulates intestinal secretion. Adenosine can also cause peripheral vasodilation and activation of nociceptors that participate in pain neural pathways.
NO bound to guanylyl cyclase NO synthase Arginine Nitric oxide Activated neuron Smooth muscle cell Rapid diffusion of NO GTP cGMP
Relaxation
Figure 16 Nitric oxide (NO) signals smooth muscle relaxation. Nitric oxide, synthesized from arginine by nitric oxide synthase, diffuses across the plasma membrane into smooth muscle cells. NO binds to and activates guanylyl cyclase which converts GTP to cGMP. cGMP causes smooth muscle relaxation. (Modied from Alberts B, Bray D, Lewis J, et al: Molecular Biology of the Cell, New York, Garland Science, 2002, p 831).

G PROTEIN-COUPLED RECEPTORS
G protein-coupled receptors (GPCRs) are seven membrane-spanning domain proteins associated with a heterotrimeric G protein (Fig. 17). The membrane regions consist of a-helical domains with a conserved structural motif.112 GPCRs contain an extracellular amino terminus and an intracellular carboxyl terminus. When stimulated by the appropriate chemical messenger, the GPCR undergoes a conformational change and couples to a specic G protein. Recently, the rst crystal structure of a GPCR has been elucidated.113 The three-dimensional structure of the rhodopsin receptor reveals a highly organized heptahelical transmembrane component with a portion of the C-terminus perpendicular to the seventh and nal membrane-spanning domains of the protein. triphosphate (ATP) within the cell cytoplasm. cAMP phosphorylates effector proteins that ultimately lead to responses such as secretion, cell movement, or growth. Receptor activation also initiates the dissociation of the a subunit from the bg subunits. However, the bg subunits remain tightly associated and themselves participate in a vast assay of cellular signals. For example, not only can bg subunits activate GPCR kinases, adenylate cyclase, and ion channels, they also induce receptor desensitization and stimulate Ras-mediated mitogen-activated protein (MAP) kinase.117,118 The Ga-GTP complex is gradually inactivated by guanosine triphosphatase (GTPase) that converts GTP to GDP. This enzymatic conversion occurs spontaneously by the G protein, which is itself a GTPase. The conversion of GTP to GDP terminates G protein stimulation of adenylate cyclase and is one way by which the basal condition is restored. Certain GPCRs activate an inhibitory G protein (Gai) that inhibits cAMP accumulation and antagonizes the effects of Gs-coupled events. In this manner, GPCRs can maintain ne control of the cellular cAMP concentration and subsequent intracellular signaling. Members of this GPCR family also activate phospholipases and phosphodiesterases, and are often involved with ion channel regulation. Other GPCRs couple with Gq and G12. The Gq family of G protein subunits regulates the production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).119 Following a-subunit dissociation, when the a subunit is in the GDP-bound form, it reassociates with bg. With re-establishment of the abg heterotrimer along with other mechanisms of desensitization, receptor signaling via the separate subunits ceases.
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G PROTEINS
G proteins are molecular intermediaries that initiate the intracellular communication process on ligand binding to its GPCR114 (Fig. 18). G proteins are composed of three subunits: a, b, and g and are classied according to their a subunit. They activate a variety of effector systems, including adenylate cyclase, guanylate cyclase, phospholipases, or specic ion channels.115 G proteins that stimulate adenylate cyclase are classied as Gs; those that inhibit adenylate cyclase are called Gi.116 When an agonist binds to a Gs-coupled receptor, a conformational change occurs, allowing the receptor to associate with the Gas subunit. Under basal (unstimulated) conditions Gas is bound to GDP; however, with hormone binding, GDP is released and is replaced with GTP. The Gs-GTP complex then activates adenylate cyclase, resulting in the generation of cAMP from adenosine
Effector Systems
Following receptor occupation, G protein subunits cause activation of enzymes or other proteins, ultimately resulting in intracellular signaling events (Table 12). Enzymes, such as adenylate cyclase or PLC, generate specic second
Extracellular Ligand Extracellular
Intracellular
Effector
Intracellular
Intracellular events
Figure 17 Molecular structure of a typical heptahelical G proteincoupled receptor. The amino terminus is extracellular and of variable length. It often contains N-linked glycosylation sites (Y) important in ligand binding. There are seven membrane-spanning domains and intracellular loops that contain sites for G protein binding and possible phosphorylation residues (open circles).
Figure 18 Hormones (ligands) bind to specic G protein-coupled receptors at a unique location within the receptor-binding pocket. On binding, the receptor conformation is altered such that a specic G protein a subunit is activated. G protein activation leads to dissociation of the a subunit from the bg subunit and activation of effector pathways. These effectors include adenylate cyclase, guanylate cyclase, ion channels, and an array of other systems.
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Table 12 Classication of G Protein a Subunits and Their Signaling Pathways
Class Gas Gai and Gao Signaling Adenylate cyclase, calcium channels Adenylate cyclase, cyclic guanosine monophosphate, phosphodiesterase, c-Src, STAT 3 Phospholipase C-b (PLC-b) Sodium/hydrogen exchange
RECEPTORS NOT COUPLED TO G PROTEINS Receptor Tyrosine Kinases

Unlike GPCRs where ligand-receptor interaction causes activation of a G protein intermediary, some ligandreceptors possess intrinsic protein tyrosine kinase activity. These membrane-spanning cell surface receptors catalyze the transfer of phosphate from ATP to target proteins. Such receptors are structurally unique in that they contain glycosylated extracellular binding domains, a single transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain contains a protein tyrosine kinase region and substrate region for agonistactivated receptor phosphorylation. With activation these receptors may phosphorylate themselves or be phosphorylated by other protein kinases.121 In general, receptor tyrosine kinases exist in the cell membrane as monomers. However, with ligand binding, these receptors dimerize, autophosphorylate, and initiate other intracellular signal transduction pathways. Most receptor tyrosine kinases couple, via ligand binding, to Ras and subsequently activate MAP kinase. MAP kinase is then able to modulate the regulation of other cellular proteins, including transcription factors. Members of the receptor tyrosine kinase family include the insulin receptor, growth factor receptors (vascular endothelial growth factor, PDGF, epidermal growth factor [EGF], broblast growth factor [FGF], insulin-like growth factor [IGF] I, macrophage-CSF, nerve growth factor), and receptors involved in development.122 Receptor tyrosine kinases are discussed further in Chapter 3 in relation to cellular growth and neoplasia. Activated tyrosine kinase receptors participate in a number of intracellular signaling events that involve the phosphorylated cytoplasmic domain. Specic phosphorylated tyrosine residues serve as binding sites for Src homology regions 2 and 3 (SH2 and SH3 domains). The result of SH2 domain binding is activation or modulation of the signaling protein that contains this binding domain. In this manner receptor tyrosine kinases activate diverse signaling pathways.123
Gaq Ga12 and Ga13
messengers such as cAMP or IP3 and DAG. Some G proteins couple directly to specic ion channels, such as potassium or calcium channels, and initiate changes in ion permeability. The effector systems are not well understood for some receptors such as those involved with cell growth and differentiation. Other G proteins such as Go may activate the phosphoinositide system. When bound to hormone, receptors that couple to Go activate PLC, which acts on inositol phospholipids found in the cell membrane. PLC can cause the hydrolysis of phosphatidylinositol-4,5bisphosphate, generating 1,2-DAG and IP3. DAG and IP3 can regulate cell metabolism by increasing intracellular calcium levels.
Receptor Desensitization
To ensure the rapidity of hormone signaling, shortly after receptor stimulation a series of events is initiated that ultimately acts to turn off signaling. The principal events in this process involve receptor desensitization and internalization, which re-establish cell responsiveness. Phosphorylation of the receptor is one of the initial events involved in turning off the signal after agonist binding and occurs through binding of arrestin-like molecules, which uncouple the receptor from the G protein.120 This uncoupling and subsequent receptor internalization (sequestration) continue the process of signal termination and eventually lead to the reestablishment of cell responsiveness.
Receptor Guanylate Cyclases

Receptor guanylate cyclases use cyclic GMP (cGMP) as a direct intracellular mediator. These cell surface receptors contain an extracellular ligand-binding region, a single transmembrane domain, and a cytoplasmic guanylate cyclase catalytic domain.124 Ligand stimulation of a receptor guanylate cyclase results in activation of cGMPdependent protein kinase, which is a serine/threonine protein kinase. The atrial natriuretic peptide (ANP) receptor is a representative receptor guanylate kinase, which mediates the potent smooth muscle relaxing activity of ANP.
Receptor Resensitization
Internalization or sequestration of the receptor occurs within minutes of receptor occupancy. Agonist-activated receptors are phosphorylated by G protein-coupled receptor kinases at specic intracellular sites which causes G protein uncoupling and initiates receptor endocytosis. GPCR endocytosis is followed by receptor dephosphorylation, recycling, and down-regulation. Chronic exposure of cells to high concentrations of hormones frequently leads to a decrease in cell surfacebinding sites. This reduction in surface receptor expression is termed down-regulation and is the result of receptor internalization. The mechanisms employed by the cell that distinguish receptor internalization and recycling from down-regulation are not clear. However, long-term agonist exposure to some receptors has been shown to activate signaling molecules that may be important in receptor down-regulation.
Nonreceptor Tyrosine Kinases

Some cell surface receptors involved in inammation and hematopoietic cell regulation work through tyrosine kinases but do not contain a cytoplasmic catalytic domain. The Src family of kinases is the primary component of this receptor signaling system.125

Receptor Tyrosine Phosphatases
Leukocyte regulation is modulated by surface receptors whose function is to remove phosphate groups from specic phosphotyrosines. CD45 is a surface protein found in white blood cells that participates in T- and B-cell activation.126 CD45 contains a single membrane-spanning domain and a cytoplasmic region with tyrosine phosphatase activity. Depending on the substrate, dephosphorylation of signaling proteins may result in reduced or enhanced activity. Receptors in this family are important in inammation and immune regulation and have been shown to participate in gastrointestinal development, growth, and cancer. normally secreted in response to food ingestion and mediate many of the nutrient effects on the gastrointestinal tract. They play a key role in cellular proliferation. Alterations in intestinal proliferation are manifest by atrophy, hyperplasia, dysplasia, or malignancy (see Chapter 3). Growth factors that have important effects on the gastrointestinal tract include peptides of the EGF family, the TGF-b family, the IGF family, the FGF family, hepatocyte growth factors, the PDGF family, trefoil factors, and many cytokines (including interleukins).128
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GROWTH FACTOR RECEPTORS

Growth factors regulate cellular proliferation by interacting with specic cell surface receptors. These receptors are membrane proteins that possess specic binding sites for the growth factor ligand. An unusual form of signaling occurs when the ligand interacts with its receptor within the same cell. For example, PDGF receptors present on the intracellular surface of broblast cell lines are activated by intracellular ligand. This process is known as intracrine signaling. Most peptide growth factors, however, interact with receptors on different cells to regulate proliferation. Growth factor receptors can be either single polypeptide chains containing one membrane-spanning region such as the receptor for EGF, or they may comprise two subunit heterodimers, with one subunit containing a transmembrane domain and the other residing intracellularly but covalently bound to the transmembrane subunit (Fig. 19). Heterodimers may also dimerize to form a receptor composed of four subunits (e.g., IGF receptor). Binding of the ligand to its receptor usually causes aggregation of two or more receptors and activation of intrinsic tyrosine kinase activity. Growth factor receptors also have the ability to autophosphorylate
Receptor Serine/Threonine Kinases

TGF-b (see Growth Factor Receptors) receptors are a unique group of surface proteins that are involved in a variety of cell functions, including chemotaxis, inammation, and proliferation. These receptors contain a single membrane domain and a cytoplasmic serine/threonine kinase region. Receptor stimulation initiates activation of the serine/threonine kinase and subsequent modulation of cellular protein function.127
REGULATION OF GASTROINTESTINAL GROWTH BY HORMONES AND TRANSMITTERS

Growth of gastrointestinal tissues is a balance between cellular proliferation and senescence. Many factors participate in maintenance of the gastrointestinal mucosa. Nutrients and other luminal factors stimulate growth of the intestinal mucosa and are necessary to maintain normal digestive and absorptive functions. Hormones and transmitters serve as secondary messengers that are
Proteoglycan
Figure 19 Growth factor receptors in the gastrointestinal tract. Schematic examples of growth factor receptor families are depicted in relation to the cell surface. Receptor regions that contain kinase activity are shown in boxes. On activation these receptors have the ability to autophosphorylate or phosphorylate other proteins to propagate intracellular cell signaling. (Modied from Podolsky DK: Peptide growth factors in the gastrointestinal tract. In Johnson LR: Physiology of the Gastrointestinal Tract. New York, Raven, 1994, p 129.)
Plasma membrane
Cytoplasm
EGF receptor
Insulin receptor IGF-I receptor
PDGF receptor
TGF-I receptor
TGF-II receptor
TGF-III receptor Tyrosine kinase Serine/Threonine kinase
18

when bound to ligand. In addition, receptor tyrosine kinase activity may phosphorylate other intracellular proteins important in signal transduction. Autophosphorylation attenuates the receptors kinase activity and often leads to down-regulation and internalization of the receptor. Mutation of the receptor at its autophosphorylation site may lead to constitutive receptor activity and cellular transformation. Growth factor receptors may couple to a variety of intracellular signaling pathways, including adenylate cyclase, phospholipase C, calciumcalmodulin protein kinases, MAP kinase, and nuclear transcription factors. Thus, growth factors play important and varied roles in most cells of the gastrointestinal tract. It is not surprising, therefore, that mutations in growth factor receptors or downstream signaling proteins can lead to unregulated cell growth and neoplasia (see Chapter 3). An important action of growth factors is their ability to modulate the expression of transacting transcription factors that can regulate expression of many other genes.129 Early response genes such as jun and fos are activated rapidly after ligand binding and control the expression of many other genes involved in cellular proliferation. Other important transcriptional factors include c-myc and nuclear factor kB (NF-kB). The latter is found in the cytoplasm in an inactive form and, following ligand binding, translocates to the nucleus where it activates other transcription factors. NF-kB is a key target for strategies to regulate cellular proliferation and inammation. Rb-1, originally identied in retinoblastoma, in its phosphorylated form is an inhibitor of cellular proliferation that complexes with the transcription factor p53. Dephosphorylation of Rb-1 releases p53, which activates other genes leading to cellular proliferation. Virtually all growth factors of the gastrointestinal tract exert paracrine effects. However, many growth factors also possess autocrine and even intracrine actions. It has recently become apparent that growth factors and other signaling molecules secreted into the lumen of the gut can have important local biological actions. Distant effects of growth factors found in the circulation may be important for growth of certain types of cancers, particularly lung and colon cancer. responsible for gastric hyperplasia in a patient with Mntriers disease.130
TRANSFORMING GROWTH FACTOR-a

Transforming growth factor (TGF)-a is produced by most epithelial cells of the gastrointestinal tract and acts through the EGF receptor. Therefore, it shares trophic properties with EGF. It is believed to play a key role in gastric reconstitution after mucosal injury. It also appears to be important in intestinal neoplasia because most gastric and colon cancers produce TGF-a (see Chapters 52 and 120).
TRANSFORMING GROWTH FACTOR-b

A family of transforming growth factor (TGF)-b peptides exerts a variety of biological actions, including stimulation of proliferation, differentiation, embryonic development, and formation of extracellular matrix.127 In contrast with the TGF-a receptor, there are three distinct TGF-b receptors (see Fig. 19).131 TGF-b modulates cell growth and proliferation in nearly all cell types and can enhance its own production from cells. It is likely that TGF-b plays a critical role in inammation and tissue repair. TGF-b augments collagen production by recruitment of broblasts through its chemoattractant properties. This action can have both benecial and deleterious effects, depending on its site of deposition and abundance. For example, TGF-b may play a key role in the development of adhesions following surgery.132
INSULIN-LIKE GROWTH FACTOR

Alternative splicing of the insulin gene produces two structurally related peptides: insulin-like growth factors (IGFs) I and II.133 IGFs signal through at least three different IGF receptors. The IGF I receptor is a tyrosine kinase, and the IGF II receptor is identical to the mannose-6-phosphate receptor. Although the exact function of IGFs in the gastrointestinal tract is not clearly understood, they have potent mitogenic activity in intestinal epithelium. IGF II appears to be critical for embryonic development.
EPIDERMAL GROWTH FACTOR

Epidermal growth factor (EGF) was the rst growth factor to be discovered. It is the prototype for a family of growth factors that are structurally related and have similarly related receptors. Other members of the family include TGF-a, amphiregulin, and heparin-binding EGF. EGF is identical to urogastrone (originally isolated from urine), which was shown to inhibit gastric acid secretion and promote healing of gastric ulcers. EGF is secreted from submaxillary glands and Brunners glands of the duodenum. It is likely that EGF interacts with luminal cells of the gastrointestinal tract to regulate proliferation. EGF has important trophic effects on gastric mucosa, and the wide distribution of EGF receptors suggests that EGF has mitogenic actions on a variety of cells throughout the gut. Recently, the EGF receptor has been reported to be
FIBROBLAST GROWTH FACTOR AND PLATELET-DERIVED GROWTH FACTOR

At least seven related broblast growth factors (FGFs) have been identied.134 These peptides have mitogenic effects on a variety of cell types, including mesenchymal cells, and likely play an important role in organogenesis and neovascularization.135 Although not unique to the gastrointestinal tract, platelet-derived growth factor (PDGF) is one of the most thoroughly studied growth factors. It is important for broblast growth, and its receptor is expressed in the liver and throughout the gastrointestinal tract, where it appears to promote wound healing.

TREFOIL FACTORS
Trefoil factors (pS2, spasmolysin, and intestinal trefoil factor, also known as TFF 1, 2, and 3, respectively) are a family of proteins that is expressed throughout the gastrointestinal tract.136 They share a common structure with six cysteine residues and three disulde bonds, creating a cloverleaf appearance that stabilizes the peptide within the gut lumen. The pS2 peptide is produced in the gastric mucosa; spasmolysin is found both in the gastric antrum and the pancreas; and intestinal trefoil factor is produced throughout the small and large intestines. These peptides are produced by mucous neck cells in the stomach or goblet cells in the intestine and are secreted onto the mucosal surface of the gut. It is likely that trefoil factors act on the apical surface of the epithelial cells, where they have growth-promoting properties on the gastrointestinal mucosa. small cell lung cancer, pancreatic cancer, and certain colon cancers.140
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REGULATION OF GASTROINTESTINAL HORMONES BY INTRALUMINAL RELEASING FACTORS

Most gastrointestinal hormones are secreted into the blood following the ingestion of a meal. However, the exact mechanism by which luminal nutrients stimulate hormone secretion is unknown. Although the apical surface of most enteric endocrine cells is exposed to the intestinal lumen (open cells), it is unclear whether nutrients interact with specic receptors on the surface of endocrine cells or whether they are absorbed and then stimulate hormone secretion. It has recently been recognized that specic releasing factors for gastrointestinal hormones are present in the lumen of the gut (Fig. 110). CCK was the rst hormone shown to be regulated by an intraluminal releasing factor.141,142 Luminal CCK-releasing factor was puried from intestinal washings and shown to stimulate CCK release when instilled into the lumen of animals. Diazepam-binding inhibitor has also been shown to stimulate CCK release, as has a pancreatic peptide known as monitor peptide.143,144 Secretin may also be regulated by an intraluminal releasing factor.25 The existence of these releasing factors underscores the signicance of bioactive peptides within the lumen of the gut.
OTHER G PROTEIN-COUPLED RECEPTORS AND GROWTH

Other peptides signaling through GPCRs may also have growth-promoting effects. Three important examples include gastrin, CCK, and gastrin-releasing peptide (GRP). Gastrin stimulates the growth of enterochromafnlike cells of the stomach and induces proliferation of the oxyntic mucosa containing parietal cells.137 Gastrin binds to CCK-2 receptors of the stomach and activates PLC and Ras pathways that ultimately result in activation of protein kinase C and MAP kinase, respectively. MAP kinase, which can also be activated by tyrosine kinase receptors typical of growth factors, causes the phosphorylation of transcription factors that are involved in cellular proliferation. In some cells, cAMP and protein kinase A exert synergistic effects on cellular growth through activation of nuclear transcription factors such as cAMP responsive element binding (protein) (CREB). However, in other cells cAMP antagonizes proliferation. Therefore, depending on the cell type, the effects of growth factors such as EGF, insulin-like growth factor (IGF), and PDGF may be enhanced by hormones that stimulate cAMP production. Certain colon cancer cells possess CCK-2 receptors and respond to the proliferative effects of gastrin. Moreover, gastrin may be produced by some colon cancers, enabling it to exert an autocrine effect to promote cancer growth.138 Whether circulating gastrin initiates colon cancer development is unknown. CCK binds preferentially to the CCK-1 type receptor, which is abundant in gallbladder, the pancreas of many species, brain, and peripheral nerves of the gut. In rodent but not human pancreas CCK causes both hypertrophy and hyperplasia of pancreatic acinar cells. Similar to the effects of gastrin, CCK activates PLC and small GTPbinding proteins to activate MAP kinase. In animal models CCK can promote pancreatic cancer growth.139 GRP (the mammalian analog of bombesin) was rst recognized for its ability to stimulate gastrin secretion from the stomach. It was later appreciated that GRP stimulates proliferation of G cells. GRP has received considerable attention recently for its growth-promoting effects on
GASTROINTESTINAL PEPTIDES THAT REGULATE SATIETY AND HUNGER

During a meal, ingested nutrients interact with cells of the mouth and gastrointestinal tract. Endocrine cells of the stomach and small intestine possess receptors that are linked to secretion of gastrointestinal hormones. GI peptides (see Chapters 17 and 18) are then released into the surrounding space where they either exert paracrine actions or are taken up into the circulation where they function as hormones. Each of these transmitters facilitates the ingestion, digestion, absorption, or distribution of nutrients that are essential for an organism. Some GI hormones control the size of an ingested meal and are known as satiety signals. Satiety hormones share several qualities.145 First, they decrease meal size. Second, blocking their endogenous activity leads to increased meal size. Third, reduction of food intake is not the result of an aversion to food. Fourth, secretion of the hormone is caused by ingestion of food that normally causes cessation of eating (Table 13). Most satiety signals interact with specic receptors on nerves leading from the gastrointestinal tract to the hindbrain. CCK is one of the most extensively studied satiety hormones. In a time- and dose-dependent manner CCK reduces food intake in both animals and humans146; an effect that is mediated by CCK-1 receptors residing on vagus nerve endings.147 The effect of CCK on food intake is a proven physiologic action because administration of a CCK receptor antagonist induces hunger and results in larger meal sizes. CCK also delays the rate at which food
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CCK-RF
Trypsin
Food
Monitor peptide
Pancreas
Figure 110 Regulation of cholecystokinin (CCK) secretion by intraluminal releasing factors. Endocrine cells containing CCK are stimulated by trypsin-sensitive releasing factors (CCK-RF) that are present in the lumen of the gut. Releasing factors secreted from the intestine are responsible for negative feedback regulation of pancreatic secretion. Under basal conditions, local trypsin inactivates CCK-RF; however, with ingestion of nutrients that compete as substrates for trypsin, CCK-RF is available to stimulate CCK secretion. The pancreatic releasing factor, monitor peptide, may contribute to sustained CCK release and pancreatic secretion after a meal.
CCK
Table 13 Gastrointestinal Peptides That Regulate Satiety and Food Intake

Reduce Meal Size Cholecystokinin (CCK) Glucagon-like peptide-1 (GLP-1) Peptide tyrosine tyrosine (PYY3-36) Gastrin releasing peptide Amylin Apolipoprotein A-IV Somatostatin Increase Meal Size Ghrelin
empties from the stomach, which may explain why the satiety actions of CCK are most apparent when the stomach is distended. Together, these ndings indicate that CCK provides a signal for terminating a meal. Glucagon-like peptide 1 (GLP-1) is produced by L cells of the ileum and colon and is released in response to food in the intestine. Although the primary action of GLP-1 is to stimulate insulin secretion it also delays gastric emptying. Moreover, infusion of GLP-1 increases satiety and produces feelings of fullness and thereby reduces food intake without causing aversion.148 GLP-1 receptors are found in the periventricular nucleus, dorsal medial hypothalamus, and arcuate nucleus of the hypothalamus, which are important areas in the regulation of hunger and like CCK, central administration of GLP-1 suppresses food intake. Peptide YY is also produced from L cells of the ileum and colon. Two forms of PYY are released into the circulation, PYY1-36 and PYY3-36. PYY1-36 binds to all subtypes of the neuropeptide Y family of receptors, whereas PYY3-36 has strong afnity for the Y2 receptor. When adminis-
tered to animals PYY3-36 causes a reduction in food intake. Mice lacking the Y2 receptor are resistant to the anorexigenic effects of PYY3-36 indicating that PYY3-36 signals satiety through this receptor.149 Recently PYY3-36 has been shown in humans to decrease hunger scores and caloric intake.150 Interestingly, most of the gastrointestinal peptide receptors that are involved in satiety are also found in the brain, where they mediate similar satiety effects. This may represent conservation of peptide signals that serve similar purposes. Leptin is referred to as an adiposity signal because it is released into the blood in proportion to the amount of body fat and is considered a long-term regulator of energy balance. Together with CCK, leptin reduces food intake and produces a greater reduction in body weight than either agent alone.78 Therefore, it appears that long-term regulators of energy balance can affect short-term regulators through a decrease in meal size that may enhance weight reduction. Hunger and initiation of a meal are intimately related. Ghrelin is intriguing because it is the only known circulating GI hormone that has orexigenic effects.93 Produced by the stomach, ghrelin levels increase abruptly before the onset of a meal and decrease rapidly after eating, suggesting that it signals initiation of a meal. Consistent with this role are studies demonstrating that administration of anti-ghrelin antibodies or a ghrelin receptor antagonist suppresses food intake.151 It is not known if ghrelin is responsible for the hunger pains and audible bowel sounds that occur in people who are very hungry.
ENTERO-INSULAR AXIS
Gastrointestinal hormones play an important role in the regulation of insulin secretion and glucose homeostasis.

These hormones control processes that facilitate the digestion and absorption of nutrients, as well as disposal of nutrients that have reached the bloodstream. In particular, gut peptides control postprandial glucose levels through three different mechanisms: (1) stimulation of insulin secretion from pancreatic beta cells, (2) inhibition of hepatic gluconeogenesis by suppression of glucagon secretion, and (3) delaying the delivery of carbohydrates to the small intestine by inhibiting gastric emptying.152 Each of these actions reduces blood glucose excursions that normally occur after eating. Approximately 50% of the insulin released after a meal is due to gastrointestinal hormones that potentiate insulin secretion.153 This interaction is known as the entero-insular axis, and the gut peptides that stimulate insulin release are known as incretins. The major incretins are glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic peptide (GIP). GLP-1 not only stimulates insulin secretion but also increases beta cell mass, inhibits glucagon secretion, and delays gastric emptying. GIP stimulates insulin secretion when glucose levels are elevated and decreases glucagon-stimulated hepatic glucose production.154 Thus, on ingestion of a meal, glucose, as it is absorbed, stimulates GLP-1 and GIP secretion. Circulating glucose then stimulates beta cell production of insulin, but this effect is substantially augmented by incretins acting in conjunction with glucose to increase insulin levels. Postprandial hyperglycemia may also be controlled by delaying the delivery of food from the stomach to the small intestine, allowing the rise in insulin to keep pace with the rate of glucose absorption. Several gut hormones that delay gastric emptying have been shown to reduce postprandial glucose excursions152 (Table 14). Amylin (islet amyloid polypeptide) is a 37 amino acid peptide synthesized primarily in the beta cells of the pancreatic islets together with insulin. Although it was originally recognized for its ability to form amyloid deposits in association with beta cell loss, it has more recently been found to suppress glucagon secretion, delay gastric emptying, and induce satiety.155 Insulin resistance in obese patients is associated with increased levels of both insulin and amylin. Type II diabetes is characterized by high circulating insulin levels and insulin resistance. In addition, insulin levels do not increase appropriately after a meal and signicant hyperglycemia occurs, which is consistent with an impaired incretin effect. GIP secretion is preserved in type II diabetes; however, the insulinotropic effect of GIP is reduced.156 Although the precise cause is unknown, the defect in GIP-stimulated insulin release is most pronounced in the late phase of insulin secretion. In contrast to GIP, GLP-1 secretion has been shown to be reduced in insulin-resistant type II diabetics. The lower GLP-1 levels are due to impaired secretion rather than increased degradation of the hormone.157 Unlike GIP, the insulin response to infusion of GLP-1 is preserved, indicating that the beta cell can respond normally to this incretin hormone. These observations suggest that GLP1 administration could be a viable treatment for the hyperglycemia associated with diabetes.158
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Table 14 Gastrointestinal Peptides That Regulate Postprandial Blood Glucose Levels

Stimulate Insulin Release Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) Gastrin releasing peptide (GRP) Cholecystokinin (CCK) (potentiates amino acid-stimulated insulin release) Gastrin (in presence of amino acids) Vasoactive intestinal peptide (VIP) (potentiates glucosestimulated insulin release) Pituitary adenylate cyclase activating peptide (PACAP) (potentiates glucose-stimulated insulin release) Motilin Delay Gastric Emptying Cholecystokinin Amylin Secretin Inhibit Glucagon Release Amylin
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Gastro-Intestinal Hormones &amp; Transmitters

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Gastrointestinal Hormones and Neurotransmitters

Regulation of Gastrointestinal Growth by Hormones and Transmitters

Other Chemical Messengers of the Gastrointestinal Tract

Section I Biology of the Gastrointestinal Tract and Liver

NEURAL REGULATION OF THE GASTROINTESTINAL TRACT

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

Muscularis mucosa Mucosal nerves Mucosa

Section I Biology of the Gastrointestinal Tract and Liver

PEPTIDE HORMONES OF THE GASTROINTESTINAL TRACT

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

Section I Biology of the Gastrointestinal Tract and Liver

VASOACTIVE INTESTINAL POLYPEPTIDE

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE

PANCREATIC POLYPEPTIDE FAMILY

Section I Biology of the Gastrointestinal Tract and Liver

SUBSTANCE P AND THE TACHYKININS

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

OTHER CHEMICAL MESSENGERS OF THE GASTROINTESTINAL TRACT

Section I Biology of the Gastrointestinal Tract and Liver

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

5HT3 Intrinsic primary afferent neuron Sensory neuron 5HT4 5HT3

Extrinsic afferent neuron

Section I Biology of the Gastrointestinal Tract and Liver

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

Extracellular Ligand Extracellular

Section I Biology of the Gastrointestinal Tract and Liver

RECEPTORS NOT COUPLED TO G PROTEINS Receptor Tyrosine Kinases

Gaq Ga12 and Ga13

Receptor Guanylate Cyclases

Nonreceptor Tyrosine Kinases

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

GROWTH FACTOR RECEPTORS

Receptor Serine/Threonine Kinases

REGULATION OF GASTROINTESTINAL GROWTH BY HORMONES AND TRANSMITTERS

Insulin receptor IGF-I receptor

TGF-III receptor Tyrosine kinase Serine/Threonine kinase

Section I Biology of the Gastrointestinal Tract and Liver

TRANSFORMING GROWTH FACTOR-a

TRANSFORMING GROWTH FACTOR-b

INSULIN-LIKE GROWTH FACTOR

EPIDERMAL GROWTH FACTOR

FIBROBLAST GROWTH FACTOR AND PLATELET-DERIVED GROWTH FACTOR

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

REGULATION OF GASTROINTESTINAL HORMONES BY INTRALUMINAL RELEASING FACTORS

OTHER G PROTEIN-COUPLED RECEPTORS AND GROWTH

GASTROINTESTINAL PEPTIDES THAT REGULATE SATIETY AND HUNGER

Section I Biology of the Gastrointestinal Tract and Liver

Table 13 Gastrointestinal Peptides That Regulate Satiety and Food Intake

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

Table 14 Gastrointestinal Peptides That Regulate Postprandial Blood Glucose Levels

Section I Biology of the Gastrointestinal Tract and Liver

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

Section I Biology of the Gastrointestinal Tract and Liver

Chapter 1 Gastrointestinal Hormones and Neurotransmitters

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Gastro-Intestinal Hormones & Transmitters

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